Asthma is a chronic disease of the airways. Despite improved treatment regimens, asthma prevalence and severity appear to be increasing in developed countries. This disease is characterized clinically by airway obstruction and airway hyperresponsiveness to a variety of stimuli such as methacholine (a cholinergic agonist that causes bronchoconstriction by stimulating the parasympathetic arm of the autonomic nervous system), and histologically by airway inflammation and edema, bronchial smooth muscle hypertrophy and mucus gland hyperplasia. Asthma is associated with allergic conditions and substantial evidence suggests that exposure to allergens in the indoor environment affects the development, persistence and severity of asthma. Recent studies also demonstrate that inhalation of bacterial components such as LPS can cause acute and chronic airflow obstruction, airway inflammation, and airway remodeling. Evidence from several recent studies suggests a role for sex hormones in modifying lung function and in the pathogenesis of asthma. Our analysis of data from two large national surveys indicates a higher prevalence of asthma among women compared to men after puberty and before menapause. Reduction in pulmonary function and worsening of asthma symptoms before and during menses has been reported. Improvements in asthma symptoms during pregnancy have been demonstrated. Oral contraceptives and hormone replacement therapy are associated with improved pulmonary function and decreased asthma exacerbation. The rise in asthma prevalence rates in the last 30 years coincides with the increased use of oral contraceptives and increased exposure to environmental chemicals with estrogenic and androgenic actions. While these studies suggest a complex relationship between sex hormones, lung function and asthma in humans, the mechanisms underlying these associations remain uninvestigated. Estrogens mediate both transcriptional and non-genomic effects via alpha or beta ERs. Both receptors are expressed in the lung but their functions in this organ are largely unknown. Mice lacking either the alpha-ER (aERKO) or the beta-ER (bERKO) were developed using gene targeting strategies. Previous studies with these mice have ascribed numerous functions in various extrapulmonary organs to either or both of the two ERs. Importantly, no studies have examined the lung phenotype of these mice under basal conditions or after environmentally relevant stimuli. Consequently the functional roles of the two ERs in the lung remains undiscovered. We found that estrogen receptor-alpha knockout mice exhibit a variety of lung function abnormalities and have enhanced airway responsiveness to inhaled methacholine under basal conditions. This is associated with reduced M2 muscarinic receptor expression and function in the lungs. Absence of estrogen receptor-alpha also leads to increased airway responsiveness without increased inflammation following allergen sensitization and challenge. These data suggest that the estrogen receptor-alpha is a critical regulator of respiration, provide a novel mechanism to explain sex hormone modulation of airway responsiveness, and identify a new therapeutic target for asthma and chronic obstructive pulmonary disease